FDA Activity Recap: January 2024 Features Major Approval, New Black Box Warnings, and Updated Guidance Documents

Last month, January 2024, the CGTLive^™ team was diligently tracking the FDA's activities related to the development of cell and gene therapies for the treatment of rare, complex, and otherwise challenging diseases and disorders.

The agency has continued to ramp up its activities around these therapies as more of them progress through the pipeline in tandem. Last month proved no different, with a surprise early approval for transfusion-dependent beta thalassemia (TDT), a request that black box warnings be added to all marketed chimeric antigen receptor T-cell therapies in the US, and the release of updated guidance documents related to the development of CAR-T and gene therapy candidates. Our team has highlighted these and other announcements below.

Click the read more buttons for more details and information about each update.

Vertex Nets Early Casgevy Approval for Transfusion-Dependent Thalassemia

January 16, 2024 — The FDA has approved Vertex Pharma and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; Casgevy) for the treatment of patients 12 years and older with TDT, over 2 months before the scheduled March Prescription Drug User Fee Act (PDUFA) date.

“Today’s approval is an important step in the advancement of an additional treatment option for individuals with beta-thalassemia, a debilitating disease that places individuals at risk of many serious health problems,” said Nicole Verdun, MD, director, Office of Therapeutic Product, Center for Biologics Evaluation and Research, FDA, said in an FDA statement. “The approval of a cell-based gene therapy for this condition using CRISPR/Cas9 technology reflects FDA’s continued commitment to supporting safe and effective treatments that leverage the most promising and cutting-edge medical technologies.”

Exa-cel is the first approved CRISPR/Cas9 gene-edited cell therapy in the US, first netting an approval for for the treatment of severe sickle cell disease (SCD) in patients aged 12 years and older with recurrent vaso-occlusive crises in December 2023. It was approved alongside bluebird bio's lovotibeglogene autotemcel (lovo-cel), marketed as Lyfgenia.

FDA Requests Black Box Warning Be Added for All Currently Approved CAR-T Therapies

January 23, 2024 — The FDA has requested that black box warnings related to secondary cancer risks be added to all 6 of the CAR-T therapy products currently approved by the agency for use in the United States. The FDA issued separate letters to each of the relevant companies for the therapies on January 19, 2024. These CAR-T products target either the antigen CD19 or B-cell maturation antigen (BCMA).

These products include Bristol Myers Squibb (BMS) and 2seventybio’s idecabtagene vicleucel (ide-cel; marketed as Abecma); BMS’s lisocabtagene maraleucel (liso-cel; marketed as Breyanzi); Janssen and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti); Novartis’s tisagenlecleucel (tisa-cel; marketed as Kymriah); Kite Pharma’s brexucabtagene autoleucel (brexu-cel; marketed as Tecartus); and Kite Pharma’s axicabtagene ciloleucel (axi-cel; marketed as Yescarta).

The language of the requested warnings takes the following form and is to be included as a Boxed Warning, noting that “T-cell malignancies may occur following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies,” with each product’s name listed in the letter.

FDA Finalizes Sets of Guidelines for Both CAR-T Products and Genome Editing Products

January 31, 2024 — The FDA has finalized 2 guidance documents focused on the development of CAR-T therapy products and gene therapy products that incorporate human genome editing, respectively.

According to a Federal Register notice, the CAR-T guidance document is the finalized version of a draft originally published in March 2022. The document covers factors relevant to the development of CAR-T products, including chemistry, manufacturing, and controls; pharmacology; toxicology; and clinical trial designs for patients with cancer. Furthermore, the document includes recommendations for both autologous and allogeneic CAR-T products, as well as other types of engineered lymphocyte therapies, such as T-cell receptor T-cell therapies and CAR natural killer cell therapies. Although, the FDA notes that because of the highly specific and unique nature of many of these other advanced lymphocyte therapy products, it may be pertinent for sponsors developing these products to discuss concerns directly with the Office of Tissues and Advanced Therapies in the Center for Biologics Evaluation and Research prior to investigational new drug (IND) application submission.

The gene therapy product guidance document is likewise the finalized version of a draft from March 2022, according to a separate Federal Register notice. Recommendations in this guidance document pertain to human gene therapy products that incorporate genome editing of human somatic cells. The guidance document is mainly focused on factors that should be covered in IND applications for these products, including product design, manufacturing, and testing; nonclinical evaluations of safety; and the design of clinical trials.

FDA Approves Kite’s Axi-Cel Manufacturing Change to Reduce Turnaround Time

January 31, 2024 — The FDA has approved Kite Pharma’s manufacturing process change for axicabtagene ciloleucel (axi-cel; Yescarta). The new change is expected to reduce median turnaround time from leukapheresis to product release from 16 days to 14 days.

“For patients with relapsed or refractory large B-cell lymphoma (LBCL), every day matters as the patient’s disease can be aggressive and worsen rapidly,” Cindy Perettie, Executive Vice President, Kite, said in a statement. “Yescarta is the first and only treatment to demonstrate superior overall survival over the standard of care as a second-line treatment with curative intent for these patients, and today’s decision by the FDA allows us to further shorten our delivery time of Yescarta so that patients have the best possible chance of survival.”

Time to treatment is an important factor in improving outcomes for patients receiving CAR T-cell therapy. Kite stated in its release that it is continuing to increase its manufacturing network capacity to meet the growing demand for axi-cel.

Janssen and Legend Biotech’s Carvykti to be Put in Front of FDA AdComm Regarding Multiple Myeloma Expanded Use BLA

January 25, 2024 — Janssen’s and Legend Biotech's ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti), which is an FDA-approved BCMA-directed autologous chimeric antigen receptor T-cell (CAR-T), will be put in front of the FDA’s Oncologic Drugs Advisory Committee (AdComm) as part of the review process for its biologics license application (BLA) for an expanded indication in adult patients with relapsed and lenalidomide-refractory multiple myeloma (MM) who have been treated with at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent. This information was revealed in a United States Securities and Exchange Commission (SEC) filing dated to January 23, 2024.

The date for the AdComm meeting has not yet been announced, but according to the SEC filing will be revealed in the Federal Register. Alongside the announcement of the FDA AdComm meeting, Legend also noted in the SEC filing that the European Medicines Agency Committee for Advanced Therapies will likewise hold a Scientific Advisory Group Oncology (SAG-O) meeting regarding the Type II variation application that the company has submitted for an expended indication in patients with relapsed and lenalidomide-refractory MM who have been treated with 1 to 3 previous lines of therapy.

The SEC filing additionally calls attention to the FDA’s recent request that black box warnings related to secondary cancer risks be added to all 6 of the CAR-T therapy products, including cilta-cel, currently approved by the agency for use in the United States. According to the FDA’s January 19, 2024, letter, the text of the boxed warning to be added to cilta-cel specifically reads: “T-cell malignancies have occurred following treatment with BCMA- and CD19- directed genetically modified autologous T-cell immunotherapies, including CARVYKTI.”